Enzyme-Inspired Chiral Secondary-Phosphine-Oxide Ligand with Dual Noncovalent Interactions for Asymmetric Hydrogenation

Article abstract of DOI:10.1002/anie.201701394

Inspired by the unique character of enzymes, we developed novel chiral SPO (secondary-phosphine-oxide) ligand (SPO-Wudaphos) which can enter into both ion pair and H-bond noncovalent interactions. The novel chiral SPO-Wudaphos exhibited excellent results

Full text of DOI:10.1002/anie.201701394

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201701394
German Edition: DOI: 10.1002/ange.201701394
Asymmetric Hydrogenation
Enzyme-Inspired Chiral Secondary-Phosphine-Oxide Ligand with
Dual Noncovalent Interactions for Asymmetric Hydrogenation
Caiyou Chen, Zhefan Zhang, Shicheng Jin, Xiangru Fan, Mingyu Geng, Yan Zhou,
Songwei Wen, Xinrui Wang, Lung Wa Chung,* Xiu-Qin Dong,* and Xumu Zhang*
Abstract: Inspired by the unique character of enzymes,
we developed novel chiral SPO (secondary-phosphine-
oxide) ligand (SPO-Wudaphos) which can enter into
both ion pair and H-bond noncovalent interactions.
The novel chiral SPO-Wudaphos exhibited excellent
results in the asymmetric hydrogenation of a-methyl-
ene-g-keto carboxylic acids, affording the chiral g-keto
acids with up to over 99% ee. A series of control
experiments and DFT calculations were conducted to
illustrate the critical roles of both the ion pair and H-
bond noncovalent interactions.
E
nzymes play vital roles in almost all metabolic
Scheme 1. a) The multiple interactions of enzymes with substrates in the
enzyme cavity. b) Ligand design. c) Coordination mode of the secondary-
phosphine-oxide (SPO) ligand with metal.
processes for providing reaction rates and selectivities
sufficient enough to sustain life.[1] Enzymes achieve
high reactivities and selectivities through multiple
cooperative noncovalent interactions with substrates,
well exemplified by ion pair, H-bond, p–p, and
hydrophobic interactions (Scheme 1a).[2] As an elegant
example, in the Claisen rearrangement of chorismate to
prephenate catalyzed by chorismate mutase, the electrostatic
character of the pericyclic transition state was stabilized by
the dual noncovalent interactions of ion pair and H-bonding
(These two interactions are the strongest among all the ones
studied[2d]), resulting in the rate accelerations up to 106.[3]
Inspired by the chorismate mutase, we anticipated that the
strong dual noncovalent interactions of ion pair and H-bond
could be utilized in a cooperative manner in the development
of new efficient chiral ligands for asymmetric hydrogenation,
resulting in significant rate accelerations and enantioselectiv-
ity improvements.
With regard to the utilization of the noncovalent ion pair
interaction, we intend to introduce the chiral Ugiꢀs amine
moiety (Scheme 3a), in which the dimethylamine function-
ality can serve as a proton acceptor to interact with the acid
substrate through the strong ion pair interaction (Sche-
me 1b).[4] At the same time, the chiral Ugiꢀs amine moiety
can be used as a versatile chiral auxiliary to conveniently
incorporate planner chirality and P-chirality.[5] On the other
hand, with regard to the utilization of the H-bonding non-
covalent interaction, we perceived that when a secondary-
phosphine-oxide (SPO) ligand coordinated to the metal, the
free hydroxy group on the phosphine atom can be formed
spontaneously (Scheme 1c).[6] As a result, the SPO ligands
afford good possibilities for the utilization of the H-bond
through the interaction of the hydroxy group with the
substrate (Scheme 1b), regardless of the fact that chiral
SPO ligands are rarely explored[7] for asymmetric catalysis
compared with the frequently used chiral diphosphine
ligands.[8] According to the above concepts, we intend to
develop a Ugiꢀs amine based chiral SPO ligand for highly
efficient asymmetric hydrogenation by exploiting two non-
covalent interactions namely the ion pair and H-bond.
With the concept of the dual ion pair and H-bond
noncovalent interactions in mind, we focused on the asym-
metric hydrogenation of a-methylene-g-keto carboxylic acids,
given the possibility that acid and ketone functionalities in a-
methylene-g-keto carboxylic acids could interact with the
proposed ferrocenyl chiral SPO ligand through ion pair and
H-bond noncovalent interactions, respectively (Scheme 1b).
[*] C. Chen, Z. Zhang, S. Jin, M. Geng, S. Wen, X. Wang, Dr. X.-Q. Dong,
Prof. X. Zhang
College of Chemistry and Molecular Sciences
Wuhan University
430072, Wuhan (P.R. China)
E-mail: xiuqindong@whu.edu.cn
xumu@whu.edu.cn
Dr. X. Fan, Dr. L. W. Chung, Prof. X. Zhang
Department of Chemistry
South University of Science and Technology of China
Shenzhen, 518000 (P.R. China)
E-mail: oscarchung@sustc.edu.cn
Y. Zhou
Department of Chemistry
The Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong SAR (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201701394.
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Moreover, a variety of valuable chiral g-keto acids could be
obtained from the asymmetric hydrogenation of a-methyl-
ene-g-keto carboxylic acids. And chiral g-keto acids can be
facilely utilized for the synthesis of many important drugs and
natural products, such as sacubitril (treatment for heart
failure)[9] and cryptophycin (a potent antimitotic antitumor
agent),[10] and natural products geodiamolide A–F[11]
(Scheme 2). However, regardless of the fact that efficient
Scheme 3. a) Preparation of the SPO-Wudaphos ligand. b) The rho-
dium complexes and the crystal structure of Rh-L2.
Scheme 2. Transformations of a-methylene-g-keto carboxylic acids into
selected drugs and natural products.
Table 1: Screening of the conditions for the asymmetric hydrogenation of
a-methylene-g-keto carboxylic acids.[a]
asymmetric hydrogenation of a-methylene-g-keto carboxylic
acids is highly desirable, to our knowledge, there are few
reports on this topic.[12] Herein, we report the first highly
efficient asymmetric hydrogenation of a-methylene-g-keto
carboxylic acids under mild and base-free reaction conditions
using a novel ferrocenyl chiral SPO ligand with cooperative
ion pair and H-bond noncovalent interactions.
The chiral ferrocenyl SPO ligand we report herein can be
easily synthesized in one-pot starting from the chiral Ugiꢀs
amine. Both of the diastereomers with a d.r. (diastereomeric
ratio) of 1:1 are obtained and can be separated simply on
silica gel and isolated as a highly air and stereochemical stable
solids (Scheme 3a). The rhodium complexes Rh-L1 and Rh-
L2 were also obtained by treating the SPO ligand with
[Rh(NBD)2]BF4 (NBD = norbornadiene) in high yield. The
structure of the rhodium complex of L2 was characterized by
X-ray analysis (Scheme 3b),[13] and the absolute configura-
tions of both diastereomers were unambiguously determined
as a result. In the rhodium complex of L2, the free hydroxy
group was generated and the complex was stabilized by the H-
bond formed between the hydroxy group with the nitrogen
atom and the solvent (EtOH).
Entry
Ligand
Solvent[c]
Conv.%[d]
ee%[e]
1
L1
L2
L1
L1
L1
L1
L1
L1
L1
L1
L1
EtOH
EtOH
MeOH
i-PrOH
CF3CH2OH
DCM
DCE
CHCl3
THF
>99
>99
>99
>99
10
>99
>99
15
99
À85
95
99
99
99
98
97
99
2[b]
3
4
5
6
7
8
9
10
11
>99
>99
>99
CH3CN
EtOAc
99
98
[a] The reaction was conducted in 0.1 mmol scale in 1.0 mL of solvent,
[Rh(NBD)2]BF4 was used as metal precursor, H2 pressure=10 bar, S/
C=200, reaction time=6 h, the configuration of the product was
determined by comparing the optical data with that reported in the
literature.[14] [b] S/C=100, reaction time=12 h. [c] DCM=dichlorome-
thane, DCE=1,2-dichloroethane. [d] Conversion of the substrate, deter-
mined by 1H NMR spectroscopy. [e] Enantiomeric excess of the product,
determined by chiral HPLC. Note, with L2 the opposite configuration is
obtained. The best result is highlighted in bold italics, the lowest
conversions are highlighted in italics.
With the chiral SPO ligands in hand, the asymmetric
hydrogenation of a-methylene-g-keto carboxylic acids was
investigated. To our delight, it was found that the chiral
ferrocenyl SPO ligand L1 was highly efficient, affording full
conversion and up to 99% ee (Table 1, entry 1). Due to the
excellent performance, we herein name the ligands as SPO-
Wudaphos. Nevertheless, the other diastereomer of the chiral
SPO-Wudaphos L2 only afforded the product with the
opposite configuration with 85% ee. Moreover, longer reac-
tion time and higher catalyst loading are required for the full
conversion of the substrate (Entry 2). These results indicated
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that the matching of the ligand with substrate is important to
results (2a–2e). And halide substituents were well tolerated;
give high enantioselectivity and reactivity. Subsequently, the
solvent effect was investigated for the asymmetric hydro-
genation of a-methylene-g-keto carboxylic acids, considering
that the noncovalent interactions of ion pair and H-bond can
be greatly affected by the solvents. It was found that there is
no significant influence of solvent on the enantioselectivities.
All the solvents gave excellent enantioselectivities (Table 1,
entries 3–11). These results indicated that the dual noncova-
lent interactions of ion pair and H-bond with the a-
methylene-g-keto acrylic acid 1a are very strong, and thus
the interaction of the ligand with substrate is not significantly
influenced by the solvent. Nevertheless, when the solvent
CHCl3 or the acidic polar protic solvent CF3CH2OH was
employed, the conversion of the substrate was very low
(Table 1, entries 5 and 8). Taking into consideration that
EtOH is environmentally benign, EtOH was selected as the
solvent for the further investigations.
With the optimized reaction conditions in hand, the
substrate scope of the asymmetric hydrogenation of a-
methylene-g-keto carboxylic acids was investigated. As
summarized in Table 2, a series of chiral g-keto acids were
obtained in full conversions and excellent ee values under
mild and base free conditions. It was found that substituents
on the phenyl ring had little influence on the hydrogenation
very high ee values were observed (up to > 99%, 2 f–2h).
Moreover, the reaction also tolerates multi-substituents on
the phenyl ring, giving the desired products with excellent
ee values (2j–2l). Furthermore, the hydrogenation results
were not significantly affected by the large steric hindrance on
the phenyl ring. For example, when methyl and the bulky
isopropyl groups were attached to the phenyl ring, an
excellent ee value was also obtained (2l). Importantly, the
alkyl substrates were well tolerated. When cyclohexyl or
cyclopropyl groups were attached to the substrate, excellent
ee values was observed (2m, 2n). Excellent ee values were
also obtained when linear n-butyl or nonlinear t-butyl groups
were introduced (2o, 2p). It is only for the naphthyl
substituted substrate that a slightly lower ee value was
observed (2i).
While the substrate scope was investigated with an S/C
ratio of 200, we decided to conduct a gram-scale reaction with
much lower catalyst loading to demonstrate the practical use
of our catalytic system. When the reaction was conducted
with 1.14 g of substrate (1a) using a catalyst loading of
0.02 mol% (S/C = 5000, THF was added to increase the
solubility) under 50 bar H2 atmosphere, the desired product
2a was obtained in 98% yield and 99% ee, demonstrating the
high reactivity of the L1-rhodium catalyst.
Several synthetic transformations were conducted to
demonstrate the practical use of the valuable chiral g-keto
acids. As shown in Scheme 4a, reduction of the ketone moiety
in 2a proceeded smoothly to give 3 in 99% yield and 97% ee.
The chiral cyclic compound 4 can be easily obtained through
the Friedel–Craft cyclization in 85% yield albeit with slight
drop of the ee value. Interestingly, when we tried to get the
chiral alcohol product through the asymmetric hydrogenation
Table 2: Substrate scope of the asymmetric hydrogenation of a-meth-
ylene-g-keto carboxylic acids.[a]
[a] The reaction was conducted in 0.1 mmol scale in 1.0 mL of EtOH,
[Rh(NBD)2]BF4 was used as metal precursor, L1 as the ligand, H2
pressure=10 bar, S/C=200, reaction time=6 h.
Scheme 4. Synthetic transformations.
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of 2a using our previously developed f-amphox ligand,[15]
in situ lactonization occurred to afford the chiral lactone 5
with the syn-configuration in high yield and excellent ee and
d.r. (Scheme 4b). The chiral lactone 6 with the anti-config-
uration was also obtained using Noyoriꢀs Ru/(R)-Xylbinap/
(R)-daipen catalyst[16] in high yield and excellent ee and d.r.
Importantly, the anti-lactone 6 can be readily converted into
compound 7 following literature procedures (Scheme 4c).[10]
Starting from 7, the potent antimitotic antitumor agent
cryptophycin can be readily synthesized.[10]
Surprisingly, when we employed the diastereomeric
mixture (1:1 ratio) of ligand L1 and L2 in the asymmetric
hydrogenation of the standard substrate 1a, the product 2a
was obtained with a good ee value (93%, Scheme 5). When
Scheme 5. Hydrogenation of 1a with diastereomeric mixtures of the
SPO ligand L1 and L2.
the ratio of L1/L2 was increased to 8:1, the product 2a with ee
up to 99% was obtained (Scheme 5), which is equal to the
result obtained when pure ligand L1 was used. Attracted by
these results, we intend to get the turnover frequencies
(TOFs) of both ligand L1 and L2 in the asymmetric hydro-
genation of 1a. It was found that L1 (TOF = 310hÀ1)
exhibited a much higher reaction rate (over 18-fold) com-
pared to L2 (TOF = 17hÀ1). As a result, good enantioselec-
tivity was observed even employing diastereomers with 1:1
ratio. These results offer the convenience that separation of
the two diastereomers of L1 and L2 is not essential to get
excellent enantioselectivities.
Scheme 6. Control experiments.
cases. These results suggest that ion pair and H-bond non-
covalent interactions are responsible for the good results
obtained using the chiral SPO-Wudaphos L1. Furthermore, it
was also revealed that the ion pair and H-bond noncovalent
interactions probably act in a cooperative manner.
To gain insights into the dual roles of the ion pair and H-
bond noncovalent interactions, several control experiments
were conducted. First of all, the critical role of the hydroxy
group (forming H-bond interaction) on the phosphine atom
was demonstrated. Changing the hydroxy group into a methyl
group or methoxy group, the ee value or conversion was
distinctly lower than the results obtained by the same
configured chiral ligand L2 (Scheme 6a).
Subsequently, base was added into the catalytic system
with L1 as the ligand to further illustrate the critical roles of
the ion pair and H-bond noncovalent interactions (Sche-
me 6b). When 0.5 equivalent of Cs2CO3 or 1 equivalent of
NEt3 was added, the hydrogenation of 1a gave rather poor
results. Considering that both Cs2CO3 and NEt3 can interfere
the noncovalent interactions of ion pair and H-bond with the
substrate, these results showed that ion pair and H-bond
noncovalent interactions are important for the excellent
performance of the chiral SPO-Wudaphos.
To shed light on the origins of the observed selectivity,
DFT (PCM B3LYP-D3/def2-SVP method) calculations have
been carried out by using the L1 ligand and substrate 1a
(Scheme 7).[17] Our solution calculations reveal that the
dimethylamine moiety interacts with the acidic group of the
substrate through a strong ion pair interaction and the
hydroxy group forms an H-bond with the ketone moiety of
the substrate in TS1R (affording the (R)-configured product)
at the same time. On the contrary, no ion pair interaction can
be formed in TS1S (giving the (S)-product), though the
ketone moiety forms an H-bond with the ammonium moiety.
As a result, TS1R is computed to be lower in free energy than
TS1S by 2.1 kcalmolÀ1 in solution (i.e. calculated 94.4% ee).
Energy decomposition analysis further shows that a larger
interaction between the substrate and metal complex
(16.7 kcalmolÀ1) is a key factor to promote the selectivity
and supports the critical roles of both the ion pair and H-bond
noncovalent interactions.
Control experiments by using the substrates 8 and 10 with
ester functionality or without the ketone functionality, so that
they cannot interact with the SPO-Wudaphos by ion pair and
H-bond interactions, respectively, were also conducted (Sche-
me 6c). Poor ee values or conversion was observed in both
In summary, a novel chiral SPO-Wudaphos ligand was
developed which can engage ion pair and H-bond noncova-
lent interactions for highly enantioselective asymmetric
hydrogenation of a-methylene-g-keto carboxylic acids,
affording the chiral g-keto acids with up to > 99% ee. The
4
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Scheme 7. Computed transition states for the migratory insertion step
(TS1R and TS1S for the L1 ligand) with relative free energies
(kcalmolÀ1) and energy decomposition of TS1S (relative to TS1R) by
the B3LYP-D3 method in solution.
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Acknowledgements
We are grateful for financial support by the grant from Wuhan
University (203273463, 203600400006), the support of the
Important Sci-Tech Innovative Project of Hubei Province
(2015ACA058), the National Natural Science Foundation of
China (Grant No. 21372179, 21432007, 21502145), and
Natural Science Foundation of Hubei Province (Grant No.
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Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric hydrogenations · ferrocene derivatives ·
noncovalent interactions · phosphine ligands · g-keto acids
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Manuscript received: February 8, 2017
Revised: March 29, 2017
ˇ
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Final Article published: && &&, &&&&
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Communications
Asymmetric Hydrogenation
Two different interactions: Just like
enzymes which can enter into multiple
cooperative noncovalent interactions
with substrates, the chiral secondary-
phosphine-oxide (SPO) Wudaphos ligand
can engage in ion pair and H-bonding
interactions. The chiral SPO-Wudaphos
ligand gave excellent results in the rho-
dium-catalyzed asymmetric hydrogena-
tion of a-methylene-g-keto carboxylic
acids.
C. Chen, Z. Zhang, S. Jin, X. Fan, M. Geng,
Y. Zhou, S. Wen, X. Wang, L. W. Chung,*
X.-Q. Dong,* X. Zhang*
&&&& — &&&&
Enzyme-Inspired Chiral Secondary-
Phosphine-Oxide Ligand with Dual
Noncovalent Interactions for Asymmetric
Hydrogenation
6
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